PMID- 26256626 OWN - NLM STAT- MEDLINE DCOM- 20170130 LR - 20170130 IS - 2214-5532 (Electronic) IS - 2214-5524 (Linking) VI - 6 DP - 2015 Jul TI - Nitric oxide-mediated bystander signal transduction induced by heavy-ion microbeam irradiation. PG - 36-43 LID - S2214-5524(15)00060-7 [pii] LID - 10.1016/j.lssr.2015.06.004 [doi] AB - In general, a radiation-induced bystander response is known to be a cellular response induced in non-irradiated cells after receiving bystander signaling factors released from directly irradiated cells within a cell population. Bystander responses induced by high-linear energy transfer (LET) heavy ions at low fluence are an important health problem for astronauts in space. Bystander responses are mediated via physical cell-cell contact, such as gap-junction intercellular communication (GJIC) and/or diffusive factors released into the medium in cell culture conditions. Nitric oxide (NO) is a well-known major initiator/mediator of intercellular signaling within culture medium during bystander responses. In this study, we investigated the NO-mediated bystander signal transduction induced by high-LET argon (Ar)-ion microbeam irradiation of normal human fibroblasts. Foci formation by DNA double-strand break repair proteins was induced in non-irradiated cells, which were co-cultured with those irradiated by high-LET Ar-ion microbeams in the same culture plate. Foci formation was suppressed significantly by pretreatment with an NO scavenger. Furthermore, NO-mediated reproductive cell death was also induced in bystander cells. Phosphorylation of NF-kappaB and Akt were induced during NO-mediated bystander signaling in the irradiated and bystander cells. However, the activation of these proteins depended on the incubation time after irradiation. The accumulation of cyclooxygenase-2 (COX-2), a downstream target of NO and NF-kappaB, was observed in the bystander cells 6 h after irradiation but not in the directly irradiated cells. Our findings suggest that Akt- and NF-kappaB-dependent signaling pathways involving COX-2 play important roles in NO-mediated high-LET heavy-ion-induced bystander responses. In addition, COX-2 may be used as a molecular marker of high-LET heavy-ion-induced bystander cells to distinguish them from directly irradiated cells, although this may depend on the time after irradiation. CI - Copyright (c) 2015 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved. FAU - Tomita, Masanori AU - Tomita M AD - Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan. Electronic address: mstomita@criepi.denken.or.jp. FAU - Matsumoto, Hideki AU - Matsumoto H AD - Division of Oncology, Biomedical Imaging Research Center, University of Fukui, 23-3 Matsuoka-Shimoaitsuki, Eiheiji-cho, Fukui 910-1193, Japan. FAU - Funayama, Tomoo AU - Funayama T AD - Microbeam Radiation Biology Group, Radiation Biology Research Division, Quantum Beam Science Center, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan. FAU - Yokota, Yuichiro AU - Yokota Y AD - Microbeam Radiation Biology Group, Radiation Biology Research Division, Quantum Beam Science Center, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan. FAU - Otsuka, Kensuke AU - Otsuka K AD - Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan. FAU - Maeda, Munetoshi AU - Maeda M AD - Radiation Safety Research Center, Central Research Institute of Electric Power Industry, 2-11-1 Iwado Kita, Komae, Tokyo 201-8511, Japan; Proton Medical Research Group, Research and Development Department, The Wakasa Wan Energy Research Center, 64-52-1 Nagatani, Tsuruga-shi, Fukui 914-0192, Japan. FAU - Kobayashi, Yasuhiko AU - Kobayashi Y AD - Microbeam Radiation Biology Group, Radiation Biology Research Division, Quantum Beam Science Center, Japan Atomic Energy Agency, 1233 Watanuki, Takasaki, Gunma 370-1292, Japan. LA - eng PT - Journal Article DEP - 20150625 PL - Netherlands TA - Life Sci Space Res (Amst) JT - Life sciences in space research JID - 101632373 RN - 0 (NF-kappa B) RN - 31C4KY9ESH (Nitric Oxide) RN - 67XQY1V3KH (Argon) RN - EC 1.14.99.1 (Cyclooxygenase 2) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) SB - IM MH - Argon MH - Astronauts MH - Bystander Effect/*radiation effects MH - Cell Communication/*radiation effects MH - Cell Death/*radiation effects MH - Cell Line MH - Cell Survival/radiation effects MH - Coculture Techniques MH - Cyclooxygenase 2/metabolism MH - DNA Breaks, Double-Stranded/radiation effects MH - DNA Repair/*radiation effects MH - Environmental Exposure/adverse effects MH - Extraterrestrial Environment MH - Fibroblasts/radiation effects MH - Heavy Ions MH - Humans MH - NF-kappa B/metabolism MH - Nitric Oxide/*metabolism MH - Phosphorylation/radiation effects MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction OTO - NOTNLM OT - Bystander response OT - Heavy ion OT - Microbeam OT - Nitric oxide OT - Non-targeted effect EDAT- 2015/08/11 06:00 MHDA- 2017/01/31 06:00 CRDT- 2015/08/11 06:00 PHST- 2015/04/23 00:00 [received] PHST- 2015/06/17 00:00 [revised] PHST- 2015/06/22 00:00 [accepted] PHST- 2015/08/11 06:00 [entrez] PHST- 2015/08/11 06:00 [pubmed] PHST- 2017/01/31 06:00 [medline] AID - S2214-5524(15)00060-7 [pii] AID - 10.1016/j.lssr.2015.06.004 [doi] PST - ppublish SO - Life Sci Space Res (Amst). 2015 Jul;6:36-43. doi: 10.1016/j.lssr.2015.06.004. Epub 2015 Jun 25.